Excessive alcohol consumption is a major risk factor for alcoholic liver disease (ALD), which manifests a spectrum of liver disorders including steatosis, steatohepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma. Alcohol related liver cirrhosis accounted for 0.9% of all global deaths and 47.9% of liver cirrhosis mortalities in 2010. The statistical numbers highlight the significance of alcohol effects on the liver pathology. However, the underlying mechanisms are still elusive and therapeutic treatments are lacking. To better understand the molecular mechanisms of ALD and identify potential drug targets, this principal investigator (PI) is investigating a critical epigenetic regulator, sirtuin 6 (Sirt6), an NAD-dependent histone deacetylase, which has been implicated in metabolism and inflammation. Sirt6 systemic knockout mice suffer chronic inflammation in multiple organs including the liver and develop progressive hepatic fibrosis. The PI's preliminary study has revealed that knockout of the Sirt6 gene in the liver significantly worsens the alcohol-induced liver injury with elevated levels of serum aspartate aminotransferase and increased expression of fibrosis markers, suggesting that Sirt6 is involved in ALD. We hypothesize that Sirt6 functions as a safeguard against the alcohol- induced liver damage. To test this hypothesis, the PI proposes to carry out the following specific aims: 1) Define the role of Sirt6 in the development of ALD; 2) Explore a novel Sirt6 pathway in the protection against the alcohol-induced liver injury. Overall, the proposed research addresses an important problem in the ALD field. Better understanding of the role of Sirt6 in ALD is expected to have significant implications for the development of prevention and treatment of this serious disease.